Pharmacological Inhibition of Inositol-Requiring Enzyme 1α RNase Activity Protects Pancreatic Beta Cell and Improves Diabetic Condition in Insulin Mutation-Induced Diabetes

Front Endocrinol (Lausanne). 2021 Oct 5:12:749879. doi: 10.3389/fendo.2021.749879. eCollection 2021.

Abstract

β-cell ER stress plays an important role in β-cell dysfunction and death during the pathogenesis of diabetes. Proinsulin misfolding is regarded as one of the primary initiating factors of ER stress and unfolded protein response (UPR) activation in β-cells. Here, we found that the ER stress sensor inositol-requiring enzyme 1α (IRE1α) was activated in the Akita mice, a mouse model of mutant insulin gene-induced diabetes of youth (MIDY), a monogenic diabetes. Normalization of IRE1α RNase hyperactivity by pharmacological inhibitors significantly ameliorated the hyperglycemic conditions and increased serum insulin levels in Akita mice. These benefits were accompanied by a concomitant protection of functional β-cell mass, as shown by the suppression of β-cell apoptosis, increase in mature insulin production and reduction of proinsulin level. At the molecular level, we observed that the expression of genes associated with β-cell identity and function was significantly up-regulated and ER stress and its associated inflammation and oxidative stress were suppressed in islets from Akita mice treated with IRE1α RNase inhibitors. This study provides the evidence of the in vivo efficacy of IRE1α RNase inhibitors in Akita mice, pointing to the possibility of targeting IRE1α RNase as a therapeutic direction for the treatment of diabetes.

Keywords: Beta cell failure; ER stress; Ire1alpha; Ire1alpha inhibition; beta cell protection; monogenic diabetes; proinsulin misfolding; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / pathology
  • Endoplasmic Reticulum Stress / genetics
  • Endoribonucleases / antagonists & inhibitors*
  • Enzyme Inhibitors / therapeutic use*
  • Gene Expression Regulation / genetics
  • Glucose Tolerance Test
  • Insulin / biosynthesis
  • Insulin / genetics*
  • Insulin-Secreting Cells / drug effects*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Protective Agents / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • Enzyme Inhibitors
  • Insulin
  • Protective Agents
  • Ern1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases